title: JAK-STAT blockade inhibits tumor initiation and clonogenic recovery of prostate cancer stem-like cells.
abstract: Interleukin (IL)-6 overexpression and constitutive STAT3 activation occur in many cancers, including prostate cancer. However, their contribution to prostate stem and progenitor cells has not been explored. In this study, we show that stem-like cells from patients with prostate cancer secrete higher levels of IL-6 than their counterparts in non-neoplastic prostate. Tumor grade did not influence the levels of expression or secretion. Stem-like and progenitor cells expressed the IL-6 receptor gp80 with concomitant expression of pSTAT3. Blockade of activated STAT3, by either anti-IL-6 antibody siltuximab (CNTO 328) or LLL12, a specific pSTAT3 inhibitor, suppressed the clonogenicity of the stem-like cells in patients with high-grade disease. In a murine xenograft model used to determine the in vivo effects of pSTAT3 suppression, LLL12 treatment effectively abolished outgrowth of a patient-derived castrate-resistant tumor. Our results indicate that the most primitive cells in prostate cancer require pSTAT3 for survival, rationalizing STAT3 as a therapeutic target to treat advanced prostate cancer.
authors.affiliation: Yorkshire Cancer Research Unit, Department of Biology, York.
authors.forename: Paula
authors.initials: P
authors.lastname: Kroon
authors.forename: Paul A
authors.initials: PA
authors.lastname: Berry
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Stower
authors.forename: Greta
authors.initials: G
authors.lastname: Rodrigues
authors.forename: Vincent M
authors.initials: VM
authors.lastname: Mann
authors.forename: Matthew
authors.initials: M
authors.lastname: Simms
authors.forename: Deepak
authors.initials: D
authors.lastname: Bhasin
authors.forename: Somsundaram
authors.initials: S
authors.lastname: Chettiar
authors.forename: Chenglong
authors.initials: C
authors.lastname: Li
authors.forename: Pui-Kai
authors.initials: PK
authors.lastname: Li
authors.forename: Norman J
authors.initials: NJ
authors.lastname: Maitland
authors.forename: Anne T
authors.initials: AT
authors.lastname: Collins
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000880:Anthraquinones / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D045744:Cell Line, Tumor; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D053612:Janus Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D019947:Receptors, Interleukin-6 / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D000880:Anthraquinones; D000911:Antibodies, Monoclonal; C508600:IL6 protein, human; C508603:IL6R protein, human; D015850:Interleukin-6; C549232:LLL12 compound; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D013449:Sulfonamides; D053612:Janus Kinases; C504234:siltuximab